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Structural Elucidation and Misassignments in Natural Products

Structural Elucidation and Misassignments in Natural Products. Daniel Newbury April 19, 2012. Overview. History of Structural Theory Classical Techniques Elucidation of Quinine Modern Spectroscopic Techniques Classical vs Current Methodology Types and Frequency of Reassignments

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Structural Elucidation and Misassignments in Natural Products

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  1. Structural Elucidation and Misassignments in Natural Products Daniel Newbury April 19, 2012

  2. Overview • History of Structural Theory • Classical Techniques • Elucidation of Quinine • Modern Spectroscopic Techniques • Classical vs Current Methodology • Types and Frequency of Reassignments • Example Structural Misassignments • Moving Forward • Conclusion

  3. Brief History of Structural Theory • 1832 ~ Organic Dualism • 1853 ~ Theory of Types Bz = C7H5O Justus von Liebig & Friedrich Wöhler HCl H2O NH3 H2 Charles-Frédéric Gerhardt

  4. Brief History of Structural Theory • 1857 ~ Tetravalence of Carbon • 1858 ~ Self-linking of Carbon • Atomic Constitution of Molecules Kekule (1858) Couper (1858) Loschmidt (1861)

  5. Classical Techniques • Physical Properties • Boiling Point • Melting Point • Density • Colour • Elemental Analysis • Qualitative Tests • Derivatization • Degradation • Total Synthesis

  6. Elucidation of Quinine • 1817 – Pelletier and Caventou • First isolation • 1853 – Pasteur • Levorotatory • 1854 – Strecker • Empirical Formula • 1856 – Perkin • Total synthesis attempt leading to Mauveine Pelletier, P. J.; Jcaventou, B. Ann. Chim. Phys. 1819, 12, 113. Pasteur, L. Compt. Rend. 1853, 37, 110 Pasteur, L. Liebigs Ann. Chem. 1853, 88, 209. Strecker, A. Liebigs Ann. Chem. 1854, 91, 155. Rabe, P.; Ackerman, E.; Schneider, W. Ber. Dtsch. Chem. Ges. 1907, 40, 3655. Rabe, P. Ber. Dtsch. Chem. Ges.1908, 41, 62

  7. Elucidation of Quinine • 1843 - Presence of two 3º Nitrogens • 1880-1892 - Presence and nature of OH-group

  8. Elucidation of Quinine • 1873-1903 - Presence of Terminal Vinyl Group • 1874-1904 - Identification of Aromatic Moiety

  9. Elucidation of Quinine • 1894 - Identity of the bicyclic moeity C8 C3 1907 Paul Rabe Correct constitution C4

  10. Elucidation of Quinine • C8 Configuration

  11. Elucidation of Quinine • C3/C4 stereochemistry Absolute Relative 1944Vladamir Prelog Relative and Absolute ›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 535. ›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 545. Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc.1944; 66(5),849.

  12. 100 Years of Elucidation ›Strecker, Liebigs Ann. Chem. 1854, 91, 155. ›G. Kerner, Jahresbericht 1869, 718. ›E. Caventou, E. Willm, Liebigs Ann. Chem. 1870, 7 (suppl),247. ›W. Zorn, J. Prakt. Chem. 1873, 8, 279. ›O. Hesse, Liebigs Ann. Chem. 1874, 174, 340. ›H.Weidel, Liebigs Ann. Chem. 1874, 173, 76. ›Z. H. Skraup, Liebigs Ann. Chem. 1879, 199, 348. ›Z. H. Skraup, G. Vortmann, Liebigs Ann. Chem. 1879, 197, 235. ›A. Baeyer, Ber. Dtsch. Chem. Ges. 1879, 12, 460. ›A. Baeyer, Ber. Dtsch. Chem. Ges. 1879, 12, 1320. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1879, 12, 97. › Z. H. Skraup, Ber. Dtsch. Chem. Ges. 1879, 12, 330. ›Z. H. Skraup, Ber. Dtsch. Chem. Ges. 1879, 12, 1104. ›O. Hesse, Liebigs Ann. Chem. 1880, 205, 314. ›Z. H. Skraup, Liebigs Ann. Chem. 1880, 201, 324. ›W. J. Comstock, W. Knigs, Ber. Dtsch. Chem. Ges. 1880, 13, 285. ›O. Hesse, Ber. Dtsch. Chem. Ges. 1881, 14, 1892. ›Z. H. Skraup, Monatsh. Chem. 1881, 2, 587. ›G. Frost, C. Bhringer, Ber. Dtsch. Chem. Ges. 1882, 15, 1659. ›H. Wiedel, Monatsh. Chem. 1882, 3, 79. ›Z. H. Skraup, Monatsh. Chem. 1883, 4, 699. ›S. Hoogewerff, W. A. Van Dorp, Rec. Trav. Chim. 1883, 2, 10. ›A. Baeyer, V. Drewsen, Ber. Dtsch. Chem. Ges. 1883, 16, 2207. ›W. Knigs, W. J. Comstock, Ber. Dtsch. Chem. Ges. 1884, 17, 1986. ›W. Knigs, W. J. Comstock, Ber. Dtsch. Chem. Ges. 1885, 18, 1223. ›Z. H. Skraup, Monatsh. Chem. 1885, 6, 762. ›O. Fischer, Jahresbericht 1885, 1014. ›W. J. Comstock,W. Knigs, Ber. Dtsch. Chem. Ges. 1887, 20, 2510. ›Z. Skraup, Monatsh. Chem. 1888, 9, 783. ›Z. H. Skraup, Monatsh. Chem. 1889, 10, 39. ›H. Schniderschitsch, Monatsh. Chem. 1889, 10, 54. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1890, 23, 2669. E. Lippmann, F. Fleissner, Monatsh. Chem. 1891, 12, 327. ›E. Lippmann, F. Fleissner, Monatsh. Chem. 1891, 12, 661. ›A. Schubert, Z. H. Skraup, Monatsh. Chem. 1891, 12, 667. ›Z. H. Skraup, Monatsh. Chem. 1891, 12, 431. ›W. Knigs,W. J. Comstock, Ber. Dtsch. Chem. Ges. 1892, 25, 1539. ›Z. H. Skraup, F. Konek von Norwall, Ber. Dtsch. Chem. Ges. 1893, 26, 1968 O. Hesse, Liebigs Ann. Chem. 1893, 276, 88. ›››Z. H. Skraup, F. Konek von Norwall, Monatsh. Chem. 1894, 15, 37 W. Knigs, Ber. Dtsch. Chem. Ges. 1894, 27, 900. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1894, 27, 1501. ›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1894, 27, 1187. ›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1894, 27, 1280. ›Z. H. Skraup, Monatsh. Chem. 1895, 16, 159. ›Z. H. Skraup, Ber. Dtsch. Chem. Ges.1895, 28, 12. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 28, 3150. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 28, 1986. ›W. Knigs, Ber. Dtsch. Chem. Ges. 1895, 30, 1326. ›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1895, 28, 1056. ›W. von Miller, G. Rohde, Ber. Dtsch. Chem. Ges. 1900, 33, 3214. ›A. Christensen, J. Prakt. Chem. 1901, 63, 330. ›Z. H. Skraup, Monatsh. Chem. 1901, 22, 1097. ›W. Pfitzinger, J. Prakt. Chem. 1902, 66, 263. ›A. Christensen, J. Prakt. Chem. 1903, 68, 430. ›A. Christensen, J. Prakt. Chem. 1904, 69, 193. ›A. Mengel, W. Knigs, Ber. Dtsch. Chem. Ges. 1904, 37, 1322. ›W. Knigs, A. Mengel, Ber. Dtsch. Chem. Ges. 1904, 37, 1328. ›W. Knigs, Liebigs Ann. Chem. 1906, 347, 172. ›P. Rabe, Liebigs Ann. Chem. 1906, 350, 180. ›P. Rabe, E. Ackerman, W. Schneider, Ber. Dtsch. Chem. Ges. 1907, 40, 3655. ›P. Rabe, Ber. Dtsch. Chem. Ges. 1908, 41, 62. ›P. Rabe, Liebigs Ann. Chem. 1909, 365, 353. ›P. Rabe, Liebigs Ann. Chem. 1909, 365, 377. ›P. Rabe, A. McMillan, Ber. Dtsch. Chem. Ges. 1910, 43, 3308. ›M. Pfannl, Monatsh. Chem. 1911, 32, 241. ›A. Kaufmann, E. Rothlin, P. Brunnschweiler, Ber. Dtsch. Chem. Ges. 1916, 49, 2302. ›P. Rabe, B. Bttcher, Ber. Dtsch. Chem. Ges. 1917, 50, 127. ›E. Jungfleisch, E. Lger, Ann. Chim. 1920, 14, 59. ›J. Kenner, Ann. Rep. Chem. Soc. 1922, 19, 157. ›L. Seekles, Rec. Trav. Chim. 1923, 42, 69. ›W. Leithe, Ber. Dtsch. Chem. Ges. 1932, 65, 660. ›K. Freundenberg, J. Am. Chem. Soc. 1932, 54, 234. ›T. Domnski, J. Suszko, Rec. Trav. Chim. 1935, 54, 481. ›T. A. Henry,W. Solomon, E. M. Gibbs, J. Chem. Soc. 1935, 966. ›E. Lger, Bull. Soc. Chim. 1938, 5, 183. ›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 535. ›V. Prelog, E. Zalan, Helv. Chim. Acta 1944, 27, 545.

  13. Role in Chemical Reaction Discovery • Structural elucidation provided driving force for novel chemical reactivity • Heterocyclic chemistry • C-C bond formation/cleavage

  14. Common Spectroscopic Era

  15. Modern Spectroscopic Techniques Vigneaud, V.; Carpenter, F. H.; Holley, R. W.; Livermore, A. H.; Rachele, J. R. Science 1946, 104(8), 431-3,450. Dickinson R. G.; Raymond A. L.. J. Am. Chem. Soc. 1923, 45, 22. Borman, S.; Russell, H.; Siuzdak, G. Today’s Chemist at Work. 2003, 5, 47-49. NMR and MRI: Applications in Chemistry and Medicine. American Chemical Society, 2001.

  16. Varian HR-30 Advertisement

  17. Classical vs Modern Techniques

  18. “While it is undeniable that organic chemistry will be deprived of one special and highly satisfying kind of opportunity for the exercise of intellectual élan and experimental skill when the tradition of purely chemical structure elucidation declines… R. B. Woodward (1963) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. Tetrahedron.1963, 19, 247-288

  19. Frequency of “Structural Revision”

  20. Types of Structural Revisions Stereochemical Revisions Rovirosa, J.; Sepulveda, M.; Quezada, E.; San-Martin, A. Phytochemistry1992, 31, 2679. Areche, C.; San-Martin, A.; Rovirosa, J.; Munoz, M. A.; Hernandez-Barragan, A.; Bucio, M. A.; Joseph-Nathan, P. J. Nat . Prod. 2010, 73, 79. Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A. J. Nat. Prod. 2008, 71, 31. Vadhadiya, P. M.; Puranik, V. G.; Ramana, C. V.; J. Org. Chem. 2012, 77, 2169−2175. Soejarto, D. D.; Fong, H. H. S.; Pezzuto, J. M. Tet. Lett. 2001, 42, 8587-8591. Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.; Stratakis, M. Chem. Eur. J., 2005, 11, 5899-5907.

  21. Types of Structural Revisions Constitutional Revisions Huang, Z.; Cai, X.; Shao, C.; She, Z.; Xia, X.; Chen, Y.; Yang, J.; Zhou, S.; Lin, Y. Phytochemistry. 2008. 69, 1604. Izuchi, Y.; Koshino, H.; Hongo, Y.; Kanomata, N,; Takahashi*, S. Org. Lett. 2011.13(13), 3360. Geraci, C.; Neri, P.; Paterno, C.; Rocco, C.; Tringali, C. J. Nat. Prod. 2000. 63, 347. Lin, D. W.; Masuda, t.; Biskup, M. B.; Nelson, J. D.; Baran*, P. S. J. Org. Chem. 2011.76(4), 1013.

  22. Suyama T. L.; Gerwick, W. H.; McPhail, K. L. Bioorg. Med. Chem. 2011, 19, 6675–6701.

  23. Suyama T. L.; Gerwick, W. H.; McPhail, K. L. Bioorg. Med. Chem. 2011, 19, 6675–6701.

  24. So What?

  25. The journey isn’t always more important than the destination • Source for Synthetic Penicillin during WWII • “More than a thousand scientists in 39 U.S. labs became involved in the project” • β-lactam Structure Unknown • Competing putative structures Penicillin Proposed Robinson (1944) Merck Scientists (IR) Crawfoot-Hodgkin (X-ray 1945) Sheehan (Synthesis 1957) Penicillin Proposed Woodward J. C. Sheehan, The Enchanted Ring: The Untold Story of Penicillin, MIT Press, Cambridge, 1984, p. 224.

  26. Biosynthetic Consequences Pummerer (1925) Barton (1955) Biosynthesis Proposed Revised

  27. Structural Misassignments and their Revisions

  28. Examples Covered in Previous Seminars Azaspiracid-1 Diazonimide A Palau’amine Hexacyclinol Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.; Yamada, Y. M. A.; tang, W.; Frederick, M. O. Angew. Chem. Int. Ed. 2004, 43, 4318 –4324. Nicolaou, K. C.; Chen D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888-12896. Seiple, I. B.; Su, S.; oung, I. S.; Lewis, C. A.; Yamaguchi, J.; Baran, P. S. Angew. Chem. Int. Ed. 2010, 49, 1095 –1098.

  29. (-)-Brevenal • Ladder frame polyether • K. brevis (marine dinoflagellate) • Non-toxic; brevotoxin family receptor antagonist Proposed (-)-Brevenal (Bourdelais 2004) Revised (-)-Brevenal (Sasaki 2006) Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005.68, 2-6. Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006.129, 16989-16999.

  30. (-)-Brevenal Structural Elucidation • FAB gave a m/z=657.4043 • C39H60O8 • 10 Double bond equivalents • 13C and DEPT confirmed 39 Carbons • 6 CH3, 12 CH2, 15 CH and 5 C • DEPT and HSQC • 5 Rings • TOCSY and COSY • 5 Spin systems. Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6. Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.

  31. (-)-Brevenal Stereochemical Elucidation Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod.2005, 68, 2-6. Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.

  32. (-)-Brevenal Structural Revision Natural (-)-Brevenal Synthesized Proposed Structure Synthesized Proposed Structure Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6. Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 129, 16989-16999.

  33. (-)-Brevenal Structural Revision Synthesized Revised Structure Bourdelais*, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M. Jr.; Baden, D. G. J. Nat. Prod. 2005, 68, 2-6. Fuwa, H.; Ebine, M., Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc.2006, 129, 16989-16999.

  34. (-)-Brevenal Biosynthetic Considerations Nakanishi, K. Toxicon 1985, 23, 473-479. Chou, H.-N.; Shimizu, Y. J. Am. Chem. Soc. 1987, 109, 2184-2185. Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989, 111, 6476-6477. Lee, M. S.; Qin, G.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234-6241.

  35. Salicylihalamide A • Macrolide • Haliclona sp. (marine Sponge) • Cytotoxicity Proposed Salicylihalamide A (Boyd 1997) Revised Salicylihalamide A (De Brabander 2000) MS, IR, 1D and 2D NMR, MM, Mosher’s Acid Total Synthesis Erickson, K. L.; Beutler, J. A.; Cardellina, J. H.; Boyd, M. R. J. Org. Chem.1997, 62, 8188–8192. Wu, Y.; Esser,L.; De Brabander, J. K. , Angew. Chem. Int. Ed. 2000, 39, 4308–4310.

  36. Mosher’s Acids

  37. Kinamycin C • Polyketide • Streptomyces murayamaensis (Bacteria) • Antibiotic and antitumor activity Revised Kinamycin C (Gould/Dmitrienko 1994) Proposed Kinamycin C (Omura 1973) MS, IR, UV, NMR, Degradation, Derivatization, X-Ray 2D-NMR, Total Synthesis Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A.; Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931 – 940. Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc.1994, 116, 2207 – 2208. Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209 – 2210.

  38. Kinamycin C Structural Revision Synthetic Analogue (Dmitrienko1990) Proposed Prekinamycin (Echavarren 1993) Possible Constitutional Isomers VS VS Dmitrienko, G. I.; Nielscn, K. E.; Steingart, C.; Ming, N. S.; Willson, J. M.; Weeratunga, G. Tet. Lett. 1990, 31, 3681-3684. Echavarren, A. M.; Tamayo, N.; Parades, M. C. TetrahedronLett. 1993, 34, 4713-4716. Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc.1994, 116, 2207 – 2208. Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209 – 2210.

  39. Kinamycin C Structural Revision • Gould, S. J.; Tamayo, N.; Melville, C. R.; Cone, M. C. J. Am. Chem. Soc.1994, 116, 2207 – 2208.

  40. Moving Forward

  41. Universal NMR database • Predictive method • relative and absolute stereochemistry • Compare chemical shift values • Structural properties of a compound are • Inherent to the specific stereochemicalarrangement of (small) substituents on it’s carbon backbone and; • Independent from the rest of the molecule Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177. Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279. Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.

  42. Universal NMR database Target Structure • Step 1: Determine Reference Structure • Step 2: Synthesize all possible diastereomers and record their chemical shifts • Not required if present in database • Step 3-5: Determine “adjusted chemical shift” • Using NMR predictive software • Eliminates influences not present in the reference structure Reference structure Oasomycin A: R=H Oasomycin B: R=A-D-Mannosyl Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177. Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279. Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.

  43. Universal NMR database • Step 6: Compare “adjusted chemical shifts” with actual reference sample values Kobayashi, Y.; Lee, J.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2177. Lee, J.; Kobayashi, Y.; Tezuka, Y.; Kishi*, Y. Org. Lett. 1999, 1, 2181. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 112, 4449. Kobayashi, Y.; Tan, C.-H.; Kishi*, Y. Angew. Chem. 2000, 39, 4279. Tan, C.-H.; Kobayashi, Y.; Kishi*, Y. Angew. Chem. Int. Ed. 2000, 39(23) 4282.

  44. Universal NMR database Oasomycin A Cruentaren B Hexacyclinol* Ampholidinol 3

  45. Conclusion

  46. Acknowledgements Prof. Louis Barriault Francis Barabé Gabriel Bellavance Genevieve Bétournay Stéphanie Lanoix Patrick Levesque Joel Marcotte Philippe McGee Mathieu Morin Dr. Guillaume Revol Travis Schwantje Boubacar Sow Past Members: Dr. David Lapointe Jason Poulin Eric Beaulieu

  47. Questions

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